The present invention relates to a new derivative of a new macrolide antibiotic, SF-837 composition (Japanese Patent Pub. No. 28834/71) which was previously discovered by the present inventors, and the invention also relates to a process for preparing the same. More particularly, the invention relates to a process for manufacturing the 9-acyl-3"-thiomethoxymethyl-SF-837 composition having the formula, ##STR1## wherein R.sub.1 represents an acetyl or propionyl group, wherein a 9,2'-diacyl derivative or a 9-acyl derivative of the SF-837 composition represented by the general formula, ##STR2## wherein R.sub.1 is defined as above and R.sub.2 represents a hydrogen atom or an acetyl or propionyl group, is treated with dimethylsulfoxide and acetic anhydride to synthesize the 9,2'-diacyl-3"-thiomethoxymethyl-SF-837 composition represented by the formula, ##STR3## wherein R.sub.1 and R.sub.2 each represents an acetyl or propionyl group, followed by alcoholysis or hydrolysis of this substance (III).
The base and known acid addition salts of the SF-837 composition, one of the macrolide antibiotics, have a peculiarly objectionable bitter taste, and the oral preparations of these substances have been used in the form of capsules or coated tablets. However, the application of these preparations in the pediatric field has been greatly avoided since they are difficult for infants and children to swallow and their manufacture is uneconomical. In such case, drugs are generally prepared and used as fruit juice suspensions or chewable tablets to exclude these defects, but the intolerable bitter taste of the SF-837 composition still makes it impossible to use this SF-837 composition in the pediatric field. Although the compound of the present invention, i.e., the 9-acyl-3"-thiomethoxymethyl-SF-837 substance, is not completely free from bitter taste, its bitterness is of such a degree as to be acceptable to infants and children. Accordingly, the compound of the present invention is very useful for making preparations for oral administration, such as powders, syrups, and troches, of low toxicity and high therapeutic effectiveness.
Furthermore, the compound of the present invention is of great use in the veterinary field as a drug for swine, which habitually refuse substances having a bitter taste.
The SF-837 substance contains three hydroxyl groups in its molecular structure, as shown in the following formula (Journal of Antibiotics, 24 460-475 (1971)). ##STR4## Further, among these three groups, those at the position C-9 and C-2' are relatively high in reactivity and various kinds of derivatives have been synthesized through them (for example, see Japanese Patent Application No. 46796/1971).
On the other side, the tertiary hydroxyl group at position C-3" is the most inactive among all of said hydroxyl groups and no derivative from this group has been demonstrated.
The present inventors have studied in various ways means for obtaining the derivatives by reaction with the hydroxyl group at this C-3" position. They have found that, when the parent substance is treated with dimethylsulfoxide and acetic anhydride, thiomethoxymethyl group can be introduced into the site of this tertiary hydroxyl group. The present invention in this manner was thus realized.
Prior to this substitutional reaction in the present invention, it was observed that the hydroxyl group at the position C-9 should be protected by acetylation or propionylation otherwise it would be oxidized to a carbonyl group under these reaction conditions; that at the position C-2' the hydroxyl group may not be protected because it can be easily acetylated by the action of the acetic anhydride added in the reaction system. Therefore, it has been found that both 9,2'-diacyl-SF-837 substance and 9-acyl-SF-837 substance are available as the starting materials of the present invention, though the former, i.e, the 9,2'-diacyl-SF-837 substance gives a higher yield.
The 9,2'-diacyl-SF-837 substance can be obtained by treating the SF-837 substance with pyridine-acetic anhydride (Journal of Antibiotics, 24 457 (1971)) or with acetylchloride-triethylamine (Japanese Patent Application No. 48096/71). The 9,2'-dipropionyl-SF-837 substance can be obtained by treating the SF-837 substance with pyridinepropionic anhydride (Journal of Antibiotics, 24 473 (1971)) or with propionyl chloride-triethylamine (Japanese Patent Application No. 48096/71). Further, the 9-acetyl-SF-837 substance, or the 9-propionyl-SF-837 substance, can be obtained by treating the SF-837 substance with acetyl chloride, or propionyl chloride, and pyridine (Japanese Patent Application No. 46796/71).